Impact Philanthropy to Improve Teaching Quality: Focus on High-Need Secondary Students

Offers models for improving teachers' skills, including through apprenticeships and in-school mentoring; for creating an environment for great teaching through better leadership and whole-school reform; and guidance for donors on the policy environment

Invest in a Strong Start for Children: A Toolkit for Donors on Early Childhood

New evidence from neuroscience and social science, high-level policy efforts, and growing concern among business, military, and other civic leaders have placed early childhood high on the priority list for donors focused on impact. Such growing interest has generated vast amounts of information and potentially useful guidance. We developed this web-based "toolkit" to help donors cut through the noise. The toolkit provides key facts, strategies, exemplar programs, and partners that any donor interested in early childhood should know.As with all of our work, our team curated these resources by reviewing the best available information from research, informed opinion, and field experience. It reflects our review of over 50 major research reports and policy analyses; dozens of conversations with experts and nonprofit leaders in the field; and engagement with two national networks of donors, researchers, and practitioners working to address early childhood issues

Noncompetitive Modulation of the Proteasome by Imidazoline Scaffolds Overcomes Bortezomib Resistance and Delays MM Tumor Growth <i>in Vivo</i>

Multiple myeloma (MM) is a malignant disorder of differentiated B-cells for which standard care involves the inhibition of the proteasome. All clinically used proteasome inhibitors, including the chemotherapeutic drug bortezomib, target the catalytic active sites of the proteasome and inhibit protein proteolysis by competing with substrate binding. However, nearly all (∼97%) patients become intolerant or resistant to treatments within a few years, after which the average survival time is less than 1 year. We describe herein the inhibition of the human proteasome <i>via</i> a noncompetitive mechanism by the imidazoline scaffold, TCH-13. Consistent with a mechanism distinct from that of competitive inhibitors, TCH-013 acts additively with and overcomes resistance to bortezomib. Importantly, TCH-013 induces apoptosis in a panel of myeloma and leukemia cell lines, but in contrast, normal lymphocytes, primary bone marrow stromal cells (hBMSC), and macrophages are resistant to its cytotoxic effects. TCH-013 was equally effective in blocking MM cell growth in co-cultures of MM cells with hBMSC isolated from CD138 negative bone marrow (BM) samples of MM patients. The cellular activity translated well <i>in vivo</i> where TCH-013 delayed tumor growth in an MM xenograft model to a similar extent as bortezomib